INCA033989 May Address Unmet Need in Mutant Calreticulin Myelofibrosis: Claire Harrison, MD

Soon after the European Hematology Association 2026 Congress, spanning June 11 to 14 in Stockholm, Sweden, The American Journal of Managed Care^® (AJMC^®) spoke with Claire Harrison, MD, who presented findings from her abstract, “Mutant Calreticulin–Specific Monoclonal Antibody, INCA033989, is Well Tolerated and Achieves Robust Spleen, Anemia, and Molecular Responses in Patients With Myelofibrosis,” at the meeting.

In part 1 of the interview, Harrison, the study’s lead author, discussed the rationale for targeting mutant calreticulin in myelofibrosis with INCA033989, an Fc-silent monoclonal antibody that binds the mutant calreticulin protein where it complexes with the thrombopoietin receptor and is displayed on the cell surface, making it a precise immunotherapeutic target.

“We've been running these studies in patients with myelofibrosis because there's significant unmet need there,” she said. “We know that our current therapies don't work well for myelofibrosis patients with calreticulin and that there are no therapies that specifically target this mutation, so it’s a perfect opportunity.”

Harrison also discussed the observed responses with INCA033989 and what they suggest about the treatment’s mechanism of action. She presented findings from 3 cohorts: patients resistant, intolerant, or refractory to a JAK inhibitor treated with monotherapy; patients with residual disease while still on a JAK inhibitor; and patients who are JAK inhibitor-ineligible.

At week 24, about half of patients considered JAK inhibitor-ineligible achieved both a 25% and 35% spleen volume reduction (SVR), outperforming the 28% to 30% SVR35 rate seen with frontline ruxolitinib in the phase 3 COMFORT-II trial (NCT00934544). Harrison added that at least a third of patients across cohorts achieved a 50% reduction in symptom burden.

Anemia responses also occurred in both patients who were JAK-naive or previously treated with JAK inhibitors, suggesting the effect was not simply attributable to a JAK inhibitor washout period. Among those considered transfusion-dependent, 4 of 6 responded, and 3 became transfusion-independent.

Additional data showed that nearly 90% of patients had some reduction in calreticulin variant allele frequency in whole blood, with deeper reductions observed in mononuclear cell subsets. Bone marrow biopsies also showed reduced fibrosis in about 40% of patients, fewer mutant-staining megakaryocytes, and increased red cell precursors, alongside a drop in circulating mutant calreticulin–positive blasts and progenitor cells.